Azheimer's (AD), the most common neurodegenerative disorder. currently affects several million people in the United States. Animal models of AD provide the best hope of deciphering the course of the disease and identifying and testing potential therapeutic targets with the ultimate goal of curing the disease. Since scientific studies have revealed that familial AD is a complex, polygenic disorder, more than one model is required to fully understand the pathogenesis of AD and develop therapeutic approaches. A major goal of the present study is to develop such models. The study will determine if transgenic mice expressing the human apolipoprotein E variant ApoE-4 and/or a mutant of human amyloid precursor protein, APPSWED will develop neuropathological alterations characteristic of AD. The APPSWED mutation is associated with a form of familial AD which may be accelerated and worsened by the coexistence of APOE-4 (gene APOE; protein ApoE). The combination of these two human proteins appro priately targeted in brains of transgenic mice may produce a particularly aggressive model for AD. Transgenic mice will be developed that overexpress the two human genes in brain, but express no mouse ApoE or APP. At appropriate ages, the mice will be tested to determine if and when they develop pathological hallmarks of AD: memory loss, decreased brain metabolism, decreased gray matter and/or increased ventricular volume and brain histopathology such as neuritic plaques and neurofibrillary tangles. The following hypothesis will be tested: Brain interactions between a mutant fl-amyloid protein and the human ApoE-4 isoform will occur in vivo in brains of transgenic mice. The interactions will lead to cognitive changes and pathological alterations in brain that will resemble hallmarks of AD. The unique transgenic mouse lines developed may furnish a particularly aggressive AD model as well as other less severe AD models. Strengths of the study are (I) a unique and rational choice of promo tors to drive expression of the transgenes, (ii) the study's ultimate transgenic mouse will carry not one, but two human AD-associated transgenes which are expected to interact and augment initiation of AD-like pathology, and (iii) the effects of expression of APOE-4 and AppsSWED will not be complicated or attenuated by the presence of the mouse APOE or APP genes.